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Background and Objectives: Anxiety and depression have implications for ischemic stroke recovery. This study explored the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke using Mendelian randomization (MR) approach., Methods: Independent genetic variants associated with anxiety and depression at genome-wide significance level ( p < 5 × 10 -8 ) were obtained from large-scale genome-wide association studies (N max = 1,306,354). Genetic results of poststroke outcome were obtained from Genetics of Ischemic Stroke Functional Outcome meta-analysis (N = 6,021). Three months after ischemic stroke event, the functional outcome was appraised with the modified Rankin Scale (mRS) score, and a mRS >2 was defined as worse functional outcome. Odds ratios (ORs) and 95% CIs are reported for the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke. The inverse-variance weighted method was adopted to pool estimates. Alternative MR methods such as the weighted median and MR using the Robust Adjusted Profile Score were used as sensitivity analyses. The intercept of MR-Egger regression was also adopted to assess pleiotropy. The heterogeneity among variants was assessed by I 2 and Q statistics., Results: Genetic liability to depression was associated with worse functional outcome after stroke (mRS 3-6, OR 2.30; 95% CI 1.18-4.49, p = 0.015). Sensitivity analyses produced consistent results. The bidirectional MR analysis indicates that poststroke outcome did not influence liability to depression (OR 1.01, 95% CI 0.99-1.03; p = 0.436). By comparison, genetic liability to anxiety was not related with poststroke outcome (OR 1.03; 95% CI 0.71-1.50; p = 0.869). Analyses in models without adjustment for stroke severity also indicated that genetic liability to depression was related with poor functional outcome after ischemic stroke (OR 2.54; 95% CI 1.41-4.58; p = 0.002). No evidence of heterogeneity or directional pleiotropy was observed ( p > 0.05)., Discussion: Our MR study provides evidence to support detrimental effects of depression on ischemic stroke functional outcome. Future studies are warranted to explore whether clinical intervention on depression can ameliorate functional outcome after ischemic stroke.